DESCRIPTION: HIV-1 Neurotoxicity: Mechanism and Modulation by Cannabinoids Synaptodendritic damage correlates with cognitive decline in patients with HIV-1-associated neurocognitive disorders (HAND). In the previous funding period, an imaging-based assay was developed to study the effects of factors released by HIV-1-infected cells on synaptic connections between hippocampal neurons. The number of excitatory synapses decreased and the number of inhibitory synapses increased following exposure to HIV-1 proteins and inflammatory cytokines. These changes were not part of the cell death process; instead, they appear to be a mechanism to cope with excess excitatory input. We hypothesize that the synaptic changes that occur during HIV-1 neurotoxicity result, in part, from an overzealous neuroprotective response and that these changes impair cognitive function. Alterations in endocannabinoid signaling are of particular relevance to HIV-1 infected patients because this system modulates neurotoxicity, because cannabinoids are given to AIDS patients clinically, and because medicinal and recreational use of marijuana by HIV-1 infected patients is high. Preliminary data demonstrate that cannabinoid signaling is altered by HIV-1-induced changes in neural networks, and that synaptic changes can be reversed. Thus, the focus of this proposal is to determine the mechanisms that underlie neuronal network adaptations resulting from exposure to HIV-1 neurotoxins. Experiments are proposed to determine the basis for the changing pharmacology observed during HIV-1 neurotoxicity and to translate in vitro findings to behavioral outcomes. Three specific aims are proposed. 1) Determine the mechanism and physiological consequences of drug-induced recovery of excitatory synapses lost during exposure to HIV-1 proteins. 2) Evaluate the effects of an increase in the number of inhibitory synapses induced by HIV-1 proteins on cell survival, network activity, and cognitive function. 3) Determine the effects of HIV-1 proteins on endocannabinoid signaling and the effects of cannabinoids on the synaptic adaptations induced by HIV-1 neurotoxins. The proposed studies will provide insight into the synaptic changes that underlie cognitive decline in HAND. Anticipated results will delineate signaling pathways that regulate synapse number during HIV-1 neurotoxicity and may identify drugs that improve cognitive function in animal models that recapitulate many of the synaptic changes in HAND. If cannabinoids impair synaptic recovery, this result would caution against medicinal and recreational use of marijuana by patients with HAND. This project will provide a foundation to guide the development of drugs to improve function in HAND patients and will identify sites where drugs of abuse might influence the formation and loss of synapses.